Therapeutic Advances in Hematology

Background: We herein report the long-term results of an allogeneic reduced-intensity conditioning (allo-RIC) protocol used in 21 consecutive patients (16 males, median age 56 years, 71% in complete remission) diagnosed with mantle cell lymphoma (MCL).

Methods: The allo-RIC consisted of fludarabine plus melphalan and peripheral blood hematopoietic stem cells (PBSCs) from human leukocyte antigen (HLA)-identical siblings were used in all cases. Median CD34+ infused cells was 5.8 × 10⁶/kg. All patients engrafted promptly.

Results: Early toxicity included mild/moderate mucositis (43%), febrile neutropenia (33%) and bacterial infections (19%). With a median follow up of 48 months, four deaths were reported, all due to infections and/or graft-versus-host disease (GVHD), yielding a 3-year cumulative incidence of nonrelapse mortality of 19.5%. Grade III–IV acute GVHD occurred in 15% and chronic GVHD in 78%, being extensive in 39%. The 5-year progression-free survival (PFS) and overall survival (OS) were both 80% (95% CI: 63–97%). Age was the only possible prognostic factor for OS, which was 43% for those aged more than 60 years and 100% for those younger (p < 0.001).

Conclusions: Our data confirm that allo-RIC offers a low toxicity profile and a chance for prolonged long-term disease-free survival in MCL, particularly in younger patients.

Aberrant JAK-STAT signaling is a hallmark of myeloproliferative neoplasms (MPNs). These hyperproliferative disorders are classically associated with activating mutations in tyrosine kinases such as JAK2 and the thrombopoietin (TPO) receptor MPL. Activation of JAK-STAT signaling and responses to JAK2 inhibitors have been observed in MPN patients lacking JAK2 or MPL mutations, suggesting that other regulatory elements in the JAK-STAT pathway are altered. However, the molecular basis for this observation has been unclear. Recently, the role of inhibitory regulators of JAK-STAT signaling in MPN pathogenesis has been increasingly recognized. LNK is an adaptor protein that forms a negative feedback loop by binding to MPL and JAK2 and inhibiting downstream STAT activation. Murine models indicate that loss of LNK function can promote the development of a MPN phenotype. Several recent studies have identified novel LNK mutations in MPNs, thus validating this notion in humans. These findings represent a novel genetic paradigm of loss of negative feedback regulation of JAK-STAT activation in MPNs and have implications for the future development of targeted therapies in MPNs.

The field of Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs) has recently witnessed tremendous advances in the basic knowledge of disease pathophysiology that followed the identification of mutations in JAK2 and MPL. These discoveries led to a revision of the criteria employed for diagnosis by the World Health Organization. The prognostic role of the JAK2 V617F mutation and of its allelic burden has been the objective of intensive research using a variety of cellular and animal models as well as in large series of patients. While a definitive position cannot yet been taken on all of the issues, there is a consensus that the presence of higher V617F allele burden, that is on the basis of a stronger activation of intracellular signalling pathways, is associated with the clinical phenotype of polycythemia vera and with defined haematological and clinical markers indicative of a more aggressive phenotype. On the other hand, a low allele burden in myelofibrosis is associated with reduced survival. Finally, a significant reduction of JAK2 V617F allele burden has been demonstrated in patients treated with interferon, while the effects of novel JAK1 and JAK2 inhibitors have not yet been fully ascertained.

Myelodysplastic syndromes (MDS) are clonal disorders of the hematopoietic system with resultant cytopenias and shortened survival. Better recognition of MDS and an aging population, some of whom have been treated with chemotherapy and radiation therapy for other cancers, is largely responsible for the growing incidence of this malignancy, which is divided into lower- and higher-risk subtypes. Erythropoiesis-stimulating agents are the first-line treatment options for patients with lower-risk MDS and symptomatic anemia or for those requiring transfusion support. Lenalidomide has been successfully used for patients with the del(5q) chromosomal abnormality who are also transfusion dependent. Hypomethylating agents, such as azacitidine and decitabine, are indicated for patients with higher-risk disease, with azacitidine demonstrating a survival advantage. Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic approach available to less than 5% of patients with MDS. Combination therapies and newer single agents targeting the important cellular pathways are being explored for treatment of MDS with promising results.

Lenalidomide, a novel immunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell lymphomas. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on preclinical models and early correlative studies conducted in parallel to clinical trials, lenalidomide has been found to enhance natural killer (NK)- and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and, to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all of these biological effects appear to play a role in the activity observed in CLL or lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the antitumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory CLL, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) treated with lenalidomide single agent. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated CLL or CLL/lymphoma patients with bulky adenopathy. Correlative studies and/or retrospective analysis of lenalidomide-treated patients had identified several biomarkers associated with clinical endpoints in CLL (i.e. changes in tumor necrosis factor alpha [TNF-α] or vascular endothelial growth factor [VEGF] levels) or DLBCL (non-GCB phenotype) patients, but need to be validated. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with rituximab in previously untreated indolent lymphoma are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting or in combination with other target-specific agents (i.e. proteasome inhibitors) in aggressive lymphomas is being addressed in ongoing clinical trials. In summary, lenalidomide is emerging as a biologically active and novel agent in the treatment of B-cell neoplasms. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory CLL or B-cell lymphomas and identify the subset of patients most likely to gain clinical benefit.